Brain function relies on information transfer between neurons at structurally and functionally defined sites called synapses. Considerable effort is directed at understanding the detailed mechanisms underlying synaptic transmission because it is increasingly clear that many diseases of the brain, including neurodevelopmental disorders and the earliest stages of neurodegenerative diseases, are associated with dysregulation of synaptic function. Synaptic transmission is composed of three components including the presynaptic release of neurotransmitter containing vesicles, diffusion of neurotransmitter through the space between neurons, and the activation of receptors that generate a response in the postsynaptic neuron. These events take place on a millisecond time scale, and the timing of each component is tightly controlled to ensure precise and efficient information transfer. Yet transmission is also highly dynamic, showing many types of plasticity in response to natural stimulus patterns. The overall goal of this project is to determine how activity controls the synchrony of neurotransmitter release from the presynaptic terminal, and how this activity-dependent plasticity contributes to the timing of information transfer through the synapse. We will first establish the conditions and mechanisms that control the synchronicity of transmitter release. We will subsequently test physiological consequences of activity dependent asynchronous transmitter release in terms of neural output and postsynaptic Ca2+ signaling. These studies will be conducted in brain slices from mice using voltage and current clamp recordings as well as calcium imaging and pharmacological manipulations. We will use a cerebellar synapse where it is well established that precise timing of synaptic transmission is critical for behaviors such as motor control and motor learning. The results from these studies will provide insight into an important presynaptic mechanism for regulating synaptic transmission that likely plays a role in neural timing throughout the CNS. PUBLIC HEALTH RELEVANCE: The timing of fast synaptic transmission is tightly controlled to ensure precise and efficient information transfer. The overall goal of this project is to determine how activity controls the synchrony of neurotransmitter release from the presynaptic terminal, and how this contributes to the timing of information transfer through the synapse.